WO1995030642A1 - Bibliotheque combinatoire de dihydrobenzopyranes - Google Patents
Bibliotheque combinatoire de dihydrobenzopyranes Download PDFInfo
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- WO1995030642A1 WO1995030642A1 PCT/US1995/005940 US9505940W WO9530642A1 WO 1995030642 A1 WO1995030642 A1 WO 1995030642A1 US 9505940 W US9505940 W US 9505940W WO 9530642 A1 WO9530642 A1 WO 9530642A1
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- lower alkyl
- aryl
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- 0 *C1(*)c(cccc2*)c2OC(*)(*)C1 Chemical compound *C1(*)c(cccc2*)c2OC(*)(*)C1 0.000 description 3
- GHPODDMCSOYWNE-UHFFFAOYSA-N Cc(cc1)cc2c1OCO2 Chemical compound Cc(cc1)cc2c1OCO2 GHPODDMCSOYWNE-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/59—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/11—Compounds covalently bound to a solid support
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
Definitions
- 93/20242 describe a synthesis wherein oligonucleotides are produced in parallel with and are chemically linked as genetic tags to oligopeptides as the compounds of interest.
- WO 93/06121 teaches methods for particle-based synthesis of random oligomers wherein identification tags on the particles are used to facilitate identification of the oligomer sequence synthesized.
- a detachable tagging system is described in Ohlmeyer et al., Proc. Natl. Acad. Sci. USA, 90, 10922- 10926, Dec. 1993.
- the present invention relates to combinatorial chemical libraries of compounds encoded with tags and to the use of these libraries in assays to discover biologically active compounds.
- the present invention also relates to libraries containing
- the present invention also relates to members of the library which interact (i.e., as agonists or antagonists) with ⁇ adrenergic receptors, dopamine receptors, ⁇ -opiate receptors, and K + channels.
- the present invention also relates to members of the library which are inhibitors of carbonic anhydrase.
- the invention also relates to methods for their preparation, intermediates, and to methods and pharmaceutical formulations for using these dihydrobenzopyrans in the treatment of mammals, especially humans. Because of their activity as inhibitors of carbonic anhydrase isozymes, compounds of the present invention are useful in the treatment of such diseases as glaucoma.
- s is a solid support
- T'-L- is an identifier residue
- -L'-II' is a ligand/linker residue
- Preferred compounds of Formula I are those wherein:
- T'-L- is of the Formula:
- n 3-12 when Ar is pentachlorophenyl
- n 3-6 when Ar is 2,4,6-trichlorophenyl
- the ligands of Formula II may be detached by photolytic, oxidative, or other cleavage techniques.
- -L'- is (b) and B is O (or
- photolytic detachment may be represented by:
- R 1 is OH, O(CH 2 ) 1-2 OH, OCH 2 CO 2 H, CO 2 H,
- R 2 is H or lower alkyl
- R 3 is H, alkyl, aryl, or arylalkyl
- R 4 and R 5 is each independently H, lower alkyl, or substituted lower alkyl where the substituents are 1-3 alkoxy, aryl, substituted aryl, carboalkoxy, carboxamido, or diloweralkylamido; or R 4 and R 5 taken together are
- R 6 and R 7 is H and the other is H, OH, or N(CH 2 ) 1-6 R 14 R 15 ; or R 6 and R 7 taken together are , , , or ;
- R 8 is H, COOR 9 , CONHR 10 , CSNHR 11 , COR 12 , SO 2 R 13, lower alkyl, aryl lower alkyl, heteroaryl, or heteroaryl lower alkyl, wherein aryl is optionally substituted with 1-3 substituents selected from lower alkyl, lower alkoxy, halo, CN, NH 2 , COOH, CONH 2 , carboalkoxy, and mono- or di- lower alkylamino and wherein heteroaryl is a mono- or bicyclic heteroaromatic ring system of 5 to 10 members including 1 to 3 heteroatoms selected from O, N, and S and 0-3 substituents selected from halo, amino, cyano, lower alkyl, carboalkoxy, CONH 2 , and S-lower alkyl;
- R 9 is lower alkyl, aryl, aryl lower alkyl, heteroaryl, aryl
- heteroaryl is a heteroaromatic ring of 5 to 6 members including 1 to 2 heteroatoms selected from O, N, and S and 0-2 substituents selected from lower alkyl, dialkylamino, lower alkoxy, and halo;
- R 10 and R 11 is each independently lower alkyl, aryl, aryl lower alkyl, or aryl substituted by 1-3 substituents selected from lower alkyl, halo, alkoxy, and haloalkyl;
- R 12 is lower alkyl, aryl, heteroaryl, aryl lower alkyl,
- heteroaryl lower alkyl a 5- or 6-membered heterocyclic ring containing 1-2 heteroatoms selected from O, S, and N, a 5- or 6-membered heterocyclic ring containing 1-2 heteroatoms selected from O, S, and N lower alkyl, or aryl substituted with 1-3 substituents selected from lower alkyl, alkoxy, halo, sulfamoyl, lower alkyl sulfamoyl, cyano, and phenyl;
- R 13 is lower alkyl, aryl, or aryl substituted with 1-3 substituents selected from lower alkyl, alkoxy, halo, CN, and haloalkyl;
- R 14 is H; alkyl substituted by 1-3 alkoxy, S-loweralkyl,
- sulfamoyl halo, alkylsulphonamido, or arylsulphonamido; alkenyl; alkynyl; aryl; substituted aryl; heteroaryl;
- R 15 is H, alkyl, -C(O)X, -C(S)X, or -C(NCN)NR 3 R 3 ;
- R 16 is lower alkyl, substituted lower alkyl, aryl, or substituted aryl;
- R 17 is H; alkyl substituted by 1-3 alkoxy, S-loweralkyl,
- sulfamoyl halo, alkylsulphonamido, or arylsulphonamido; alkenyl; alkynyl; aryl; substituted aryl; heteroaryl;
- X is alkyl, aryl, arylalkyl, O-loweralkyl, or NR 3 R 3
- Z is -(CH 2 ) 1-6 -, optionally substituted with 1-3 lower alkyl;
- n 2 or 3;
- n 4-9;
- Preferred compounds of Formula II are those wherein R 12 is sulfamoylphenyl, most preferably p-sulfamoylphenyl.
- a preferred embodiment of the invention is a compound of
- R 1 is OH, OCH 2 C(O)NH(CH 2 ) 1-6 R 14 , or OCH 2 -4-Phe- C(O)NH(CH 2 ) 1-6 R 14 ;
- R 2 is H or lower alkyl; R 4 and R 5 is each lower alkyl; or R 4 and R 5 taken together are
- R 8 is H, COOR 9 , CONHR 10 , CSNHR 11 , COR 12 , SO 2 R 13 , .
- R 9 is lower alkyl, aryl lower alkyl, aryl, tetrahydrofuranyl, tetrahydropyranyl, or aryl substituted by 1 to 2 substituents selected from lower alkyl, alkenyl, alkoxy, methylene dioxy, and halo;
- R 10 and R 11 is each independently aryl, aryl lower alkyl, or aryl
- R 12 is lower alkyl, aryl, aryl lower alkyl, heteroaryl lower alkyl wherein the heteroatoms are N, a 5- or 6-membered heterocyclic ring containing 1-2 heteroatoms selected from S and N lower alkyl, or aryl substituted with 1 substituent selected from lower alkyl, alkoxy, halo, sulfamoyl, cyano, or phenyl;
- R 13 is lower alkyl, aryl, or aryl substituted with 1 substituent selected from lower alkyl, alkoxy, and halo; or a pharmaceutically acceptable salt thereof.
- Most preferred compounds of the invention are represented by the formula:
- R 1 is 6- or 7-OH
- R 2 is H or lower alkyl
- R 4 and R 5 is each methyl; or R 4 and R 5 taken together are -(CH 2 ) 5 -,
- R 8 i is H, COOR 9 , CONHR 10 , CSNHR 1 1 , COR 12 , SO 2 R 13 , benzyl, -CH 2 -Ph-4-F, -CH 2 -Ph-4-OCH 3 , -CH 2 -4-Py, n-butyl, -CH 2 -c-propyl, , or
- R 9 is i-propyl, phenyl, phenethyl, t-butyl,
- R 10 is phenyl, p-chlorophenyl, or p-trifluoromethylphenyl
- R 11 is phenyl, benzyl, or 1-naphthyl
- R 12 is , , , , , , ,
- R 13 is 1- or 2-naphthyl, phenyl, 4-chlorophenyl, 4- methylphenyl, 4-t-butylphenyl, n-butyl, or i-propyl;
- R 1 is 6- or 7-OH when R 2 is H;
- R 1 is 7-OH when R 2 is CH 3 ;
- R 4 and R 5 is each methyl; or R 4 and R 5 taken together are -(CH 2 ) 5 -,
- R 1 is 6- or 7-OCH 2 C(O)NH(CH 2 ) 1-6 R 17 , or 6- or 7-OCH 2 -4- Phe-C(O)NH(CH 2 ) 1-6 R 17 when R 2 is H;
- R 1 is 7-OCH 2 C(O)NH(CH 2 ) 1-6 R 17 , or 7-OCH 2 -4-Phe- C(O)NH(CH 2 ) 1-6 R 17 when R 2 is CH 3 ;
- R 4 and R 5 is each methyl; or R 4 and R 5 taken together are -(CH 2 ) 5 -,
- R 8 is H, CONHCH 3 , SO 2 Ph, (CH 2 ) 3 CH 3 , CO(CH 2 ) 2 CH 3 , benzyl, -C(O)-(4-Phe)-SO 2 NH 2 , or ;
- R 13 is
- R 14 is methyl, n-butyl, 3-methoxy-n-propyl, CH 2 -c-propyl, or
- R 17 is methyl, 2-methoxyethyl, 2-phenylethyl,
- inhibitors of carbonic anhydrase are compounds of formulae IIb, IIc, and IId:
- R 1 is 6- or 7-OH, 6- or 7-OCH 2 C(O)NH(CH 2 ) 1-6 R 17 , or
- R 2 is H or CH 3 ;
- R 8 is -CO-Ph-p-SO 2 NH 2 ;
- R 14 and R 17 may each be any pharmacologically relevent orgaic radical, such as those derived by removal of H 2 NCH 2 - from the following compounds:
- an aspect of the invention is a method of identifying a compound having a desired characteristic which comprises synthesizing a combinatorial library of Formula I and testing the compounds of Formula I and the ligands of Formula II, either attached to the solid support or detached therefrom, in an assay which identifies compounds having the desired
- a further embodiment of the invention is determining the structure of any compound so identified.
- R 2 is H or lower alkyl
- R is allyl or methyl and b) when R is allyl reacting said compound with methylene chloride, tetrakistriphenylphosphine palladium(0), and pyrrol idine and stirring the mixture at 0°C, or when R is methyl reacting said compound with dilute NaOH and THF and stirring the mixture at 0°C.
- R allyl is preferable to the t-butyl or methyl esters since the milder conditions would not induce aldol type condensation of the acetophenone portion of the molecule.
- Another embodiment of the invention is a method for identifying compounds that are inhibitors of carbonic anhydrase which comprises preparing a mixture of 20-300 pmol test compound and aqueous solutions (total volume: 25-100, preferably about 50, ⁇ L) of 0.03-0.12, preferably about 0.06, ⁇ M carbonic anhydrase and 0.04- 0.16, preferably about 0.08, ⁇ M dansylamide, exposing said mixture to U.V. (preferably 274 nm) light, and determining the amount of emitted U.V. (preferably 454 nm) light.
- U.V. preferably 274 nm
- U.V. preferably 454 nm
- Another embodiment of the invention is a method for identifying compounds that are enzyme inhibitors which is a lawn assay which comprises contacting a colloidal matrix containing enzyme, which matrix has embedded therein a mono-layer of solid supports with attached ligands, with a layer of fluorogenic substrate-containing material, eluting said ligands by exposure to U.V. light, and detecting zones of inhibition in the colloidal matrix produced thereby.
- a preferred such lawn assay comprises contacting an agarose matrix containing bovine carbonic anhydrase with a fluorescein diacetate-containing layer of agarose.
- s is a solid support
- R is H or alkyl
- R 16 is lower alkyl, substituted lower alkyl, aryl, or substituted aryl;
- R 17 is H; alkyl substituted by 1-3 alkoxy, S-loweralkyl,
- sulfamoyl halo, alkylsulphonamido, or arylsulphonamido; alkenyl; alkynyl; aryl; substituted aryl; heteroaryl;
- Y is aryl or heteroaryl.
- Compounds of formula 14 are useful as intermediates in the construction of combinatorial libraries and are especially useful in automated or batch mode syntheses thereof.
- Boc t-butyloxycarbonyl
- DBU 1,8-diazabicyclo[5,4,0]undec-7-ene
- FACS fluorescence activated cell sorting
- HOBt N-hydroxybenzotriazole
- PEG polyethylene glycol
- Ph phenyl
- Alkyl is intended to include linear, branched, or cyclic structures and combinations thereof of from 1 to 20 carbon atoms.
- “Lower alkyl” includes alkyl groups of from 1 to 8 carbon atoms.
- lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, octyl, c-propyl, c-butyl and the like.
- Lower cycloalkyl includes cycloalkyl groups of from 3 to 8 carbon atoms. Examples of lower cycloalkyl groups include c-propyl, c-butyl, c-pentyl, 2-methylcyclopropyl, cyclopropylmethyl, and the like.
- Alkenyl is C 2 -C 6 alkenyl of a linear, branched, or cyclic
- alkenyl groups include allyl, isopropenyl, pentenyl, hexenyl, c-hexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
- Alkynyl is C 2 -C 6 alkynyl of a linear, branched, or cyclic (C 5 -C 6 ) configuration and combinations thereof.
- alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl isopropynyl, pentynyl, hexynyl, c-hexynyl, 1-propynyl, 2-butynyl, 2-methyl-2-butynyl, and the like.
- Alkoxy means alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
- Substituted loweralkyl means lower alkyl substituted with 1-3 alkoxy, carboalkoxy, carboxamido, di-loweralkylamino, aryl, substituted aryl, or heteroaryl.
- Aryl means phenyl or naphthyl.
- Substituted aryl means aryl substituted with 1-3 halo, loweralkyl, alkoxy, aryl, S-loweralkyl, alkylsulphonamido,
- Heteroaryl means a 5 or 6 membered aromatic ring containing 1-3 hetero atoms selected from O, N, and S.
- Substituted heteroaryl means heteroaryl substituted with 1-3 halo, loweralkyl, alkoxy, aryl, S-loweralkyl, alkylsulphonamido, arylsulphonamido, or sulfamoyl.
- Heterocycloalky means lower cycloalkyl containing 1-3 hetero atoms selected from O, N, and S.
- Halogen includes F, Cl, Br, and I.
- L and L' are depicted in Table 1 , which also shows cleavage reagents.
- the left-hand bond is the point of attachment to the solid support and the right-hand bond is the point of attachment to either T or II.
- the tags of this invention, T are chemical entities which possess several properties: they must be detachable from the solid supports, preferably by photolysis or oxidation; they must be
- the tags may be structurally related or unrelated, e.g., a homologous series, repetitive functional groups, related members of the Periodic Chart, different isotopes, combinations thereof, and the like. At the end of the combinatorial synthesis, to each solid support, there will usually be attached at least 0.01 femtomol, usually 0.001-50 pmol, of each tag.
- the tags may be aliphatic, alicyclic, aromatic, heterocyclic, or combinations thereof.
- Distinguishing features may be the number of repetitive units, such as methylene groups in an alkyl moiety; alkyleneoxy groups in a
- polyalkyleneoxy moiety halo groups in a polyhalo compound; ⁇ -and/or ⁇ -substituted ethylene groups where the substituents may be alkyl groups, oxy, carboxy, amino, halo, or the like; isotopes; etc.
- solid supports The materials upon which the combinatorial syntheses of the invention are performed are referred to as solid supports, beads, and resins. These terms are intended to include:
- beads, pellets, disks, fibers, gels, or particles such as cellulose beads, controlled pore-glass beads, silica gels, polystyrene beads optionally cross-linked with divinylbenzene and optionally grafted with polyethylene glycol and optionally functionalized with amino, hydroxy, carboxy, or halo groups, grafted co-poly beads, polyacrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N,N'-bis-acryloyl ethylene diamine, glass particles coated with hydrophobic polymer, etc., i.e., material having a rigid or semi-rigid surface; and
- soluble supports such as low molecular weight non-cross-linked polystyrene. It is intended that the definitions of any substituent or symbol (e.g., R 3 ) in a particular molecule be independent of its definitions elsewhere in the molecule. Thus, NR 3 R 3 represents NH 2 , NHCH 3 , N(CH 3 ) 2 , etc.
- Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R) or (S).
- the present invention is meant to comprehend all such possible diastereomers as well as their racemic and optically pure forms and mixtures thereof.
- Optically active (R) and (S) forms may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
- the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.
- compositions of the present invention comprise a compound of Formula II as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and, optionally, other therapeutic ingredients.
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including organic and inorganic acids or bases.
- salts may be prepared from pharmaceutically acceptable non-toxic bases. Salts derived from all stable forms of inorganic bases include
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
- ethylenediamine N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc.
- salts may be prepared from pharmaceutically acceptable non-toxic acids.
- acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, etc.
- Particularly preferred are citric, hydrobromic, maleic, phosphoric, sulfuric, and tartaric acids.
- the ability of the compounds of Formula II to interact with ⁇ adrenergic receptors indicates that the compounds are useful to treat, prevent, or ameliorate hypertension and benign prostate hypertrophy in mammals, especially in humans.
- the ability of the compounds of Formula II to interact with dopamine receptors indicates that the compounds are useful to treat, prevent, or ameliorate Alzheimer's disease and depression in humans.
- the ability of the compounds of Formula II to interact with ⁇ -opiate receptors indicates that the compounds are useful to treat, prevent, or ameliorate schizophrenia in mammals, especially in humans.
- K + channels indicates that the compounds are useful to treat, prevent, or ameliorate hypertension, asthma, and pulmonary insufficiency in mammals, especially in humans.
- the magnitude of the prophylactic or therapeutic dose of the compounds of Formula II will vary with the nature and severity of the condition to be treated and with the particular compound of
- the daily dose range for anti-enzymic use lies in the range of 20 to 0.001 mg/kg body weight of a mammal, preferably 10 to 0.01 mg/kg, and most preferably 1.0 to 0.1 mg/kg, in single or divided doses. In some cases, it may be necessary to use doses outside these ranges.
- a suitable daily dosage range is from about 10 to 0.0005 mg (preferably 5 to 0.01 mg) compound of Formula II per kg body weight.
- a suitable daily dosage range is from about 20 to 0.001 mg (preferably 10 to 0.01 mg) compound of Formula II per kg body weight.
- a suitable daily dosage range is from about 10-0.01 %
- compound of Formula II typically prepared as a 2.0-0.1 % by weight solution or suspension of a compound of Formula II in an acceptable ophthalmic formulation.
- the compounds of Formula II may also be used in combination with other pharmaceutically active ingredients.
- a typical ocular formulation may comprise the compound alone or in combination with a ⁇ -adrenergic blocking agent such as timolol maleate or a parasympathomimetic agent such as pilocarpine.
- a ⁇ -adrenergic blocking agent such as timolol maleate or a parasympathomimetic agent such as pilocarpine.
- the two active ingredients are present in approximately equal parts.
- Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of Formula II.
- a route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of Formula II.
- oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. routes may be employed.
- Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
- compositions of the present invention comprise a compound of Formula II, or a pharmaceutically acceptable salt thereof, as an active ingredient, and may also contain a
- compositions include compositions suitable for oral, rectal, topical (including transdermal devices, aerosols, creams, ointments, lotions, and dusting powders), parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration;
- a compound of Formula II may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending on the nature of the preparation desired for administration, i.e., oral, parenteral, etc.
- any of the usual pharmaceutical media may be used, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (e.g., suspensions, elixirs, and solutions); or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc.
- capsules in the case of oral solid preparations such as powders, capsules, and tablets. Solid oral preparations are preferred over liquid oral preparations. Because of their ease of administration, tablets and capsules are the preferred oral dosage unit form. If desired, capsules may be coated by standard aqueous or non-aqueous techniques.
- the compounds of Formula II may be administered by controlled release means and devices such as those described in U.S.P. Nos. 3,536,809; 3,598,123; 3,630,200; 3,845,770; 3,916,899; and 4,008,719, which are incorporated herein by reference.
- compositions of the present invention suitable for oral administration may be prepared as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient in powder or granular form or as a solution or suspension in an aqueous or nonaqueous liquid or in an oil-in-water or water-in-oil emulsion.
- Such compositions may be prepared by any of the methods known in the art of pharmacy. In general, the compositions are prepared by uniformly and intimately admixing the active
- a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granule optionally mixed with a binder, lubricant, inert diluent, or surface active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
- Ophthalmic inserts are made from compression molded films which are prepared on a Carver Press by subjecting the powdered mixture of active ingredient and HPC to a compression force of 12,000 lb. (gauge) at 149°C for 1-4 min. The film is cooled under pressure by having cold water circulate in the platen. The inserts are then
- each insert is placed in a vial, which is then placed in a humidity cabinet (88% relative humidity at 30°C) for 2-4 days. After removal from the cabinet, the vials are capped and then autoclaved at 121°C for 0.5 hr.
- These compounds of Formulae I and II may also be used as libraries for discovering new lead structures by evaluation across an array of biological assays, including the discovery of selective inhibition patterns across isozymes. These libraries are thus tools for drug discovery; i.e., as a means to discover novel lead compounds by screening the libraries against a variety of biological targets and to develop structure-activity relationships in large families of related compounds.
- the libraries may be tested with the ligands attached to the solid supports as depicted in Formula I or the individual compounds II may be detached prior to evaluation.
- screening assays such as FACS sorting, bead lawn assays, and cell lawn assays may be used.
- the compounds of the present invention may be tested by assays well known in the art for interaction with ⁇ adrenergic
- carbonic anhydrase inhibition assays are: Carbonic Anhydrase Inhibition - Maren and Couto, "The
- Carbonic Anhydrase Inhibition It has now been found that the use of very low initial concentrations (0.04-1.6, preferably about 0.6, ⁇ M) of dansylamide and (0.03-1.2, preferably about 0.3, ⁇ M) of carbonic anhydrase to assay test compounds for carbonic anhydrase inhibition not only allows the use of very small total volumes (approx. 25-100, preferably about, 50 ⁇ L) per assay but also allows one to distinguish high-affinity from low-affinity compounds without either re-elution or re-synthesis of the test compound.
- Reactions are carried out in 50 ⁇ L total volume in 96-well plates, preferably, Dynatech MicroFluor plates, white with 'U' bottom, containing the test compounds.
- the assay mix is prepared immediately before use, and 50 ⁇ L of the assay solution is pipetted into each well of plates in which the test compounds are previously dried. The plates are spun briefly in a tabletop centrifuge before reading fluorescence.
- Fluorescence is read in a Perkin-Elmer LS 50B spectrofluorimeter fitted with a Well Plate Reader Accessory using an excitation
- An enzyme of interest is incorporated into a gellable gum such as silica gel, agar, agarose, pectin, polyacrylamide, gelatin, starch, and gellan gum, preferably a low melting-temperature agarose gel (0.5-2.0%, wt./vol.), which is layered on top of a lawn, no greater than one bead in thickness, of solid supports with attached ligands.
- a gellable gum such as silica gel, agar, agarose, pectin, polyacrylamide, gelatin, starch, and gellan gum, preferably a low melting-temperature agarose gel (0.5-2.0%, wt./vol.), which is layered on top of a lawn, no greater than one bead in thickness, of solid supports with attached ligands.
- the detection of an active combinatorial library member is accomplished by photoeluting the ligands from the beads in situ by exposure to U.V. light. To minimize premature photoelution,
- the beads are evaluated by placing a second layer, preferably low-melt agarose gel, containing a substrate on top of the one containing the enzyme and the photoreleased library members, and allowing enzymic conversion of substrate into product by diffusion of the substrate into the enzyme-containing gel.
- the substrate is preferably one that produces a photometric change upon conversion into product; e.g., the generation of a colored product, a fluorescent product, or a chemiluminescent reaction (where one of the products is a photon).
- the second layer may comprise a gellable gum such as silica gel, agar, agarose, pectin, polyacrylamide, gelatin, starch, and gellan gum, or a solid material such as a matrix containing an array of fluorogenic-pellets.
- a gellable gum such as silica gel, agar, agarose, pectin, polyacrylamide, gelatin, starch, and gellan gum
- a solid material such as a matrix containing an array of fluorogenic-pellets.
- This technique may be used with a variety of enzymes, for example:
- a bead lawn assay for testing carbonic anhydrase inhibition preferably comprises agarose for both layers, bovine carbonic anhydrase, and fluorescein diacetate.
- Bead Lawn Assay (Carbonic Anhydrase). Beads to be tested are arrayed in a minimal amount of methanol in a 60 mm polystyrene tissue culture dish and then all the methanol allowed to evaporate. A 2.5% (wt./vol.) mixture of agarose (SeaPlaque, FMC BioProducts, Rockland, ME) in 20 mM sodium phosphate buffer (pH 7.4) is heated on a hot plate until the agarose dissolves and then is equilibrated to 37°C in a water bath. A separate stock of the same buffer is also equilibrated to 37°C.
- the enzyme layer is prepared as follows: 100 ⁇ L of a bovine carbonic anhydrase stock (0.5 mg/mL or 53 ⁇ M based on absorbance at 280 nm, Sigma #C-3934) is added to 2.15 mL of buffer, and 1.25 mL agarose solution is added to the mixture. The agarose/enzyme solution is poured onto the dish containing the beads and the agarose is allowed to solidify at r.t. for 3-5 min. To identify zones of inhibition, the compounds, which are optionally photoeluted by exposure to 4.7-6 mW/cm 2 365 nm UV light for 5 sec.
- FLDA fluorescein diacetate
- the buffer used is 20 mM Tris, 1 mM EGTA, pH 7.8.
- the enzyme layer contains 1 mg/mL recombinant human inositol monophosphatase (purified from E. col ⁇ ) and 10 mM MgCl 2 .
- the preferred substrate is CSPD.
- the compounds of the present invention can be prepared according to the following methods.
- each solid support upon which a compound is being synthesized is uniquely tagged to define the particular chemical event(s) occurring during that step.
- the tagging is accomplished using identifiers such as those of Formula IV, which record the sequential events to which the support is exposed during the synthesis, thus providing a reaction history for the compound produced on each support.
- the identifiers are used in combination with one another to form a binary or higher order encoding scheme permitting a relatively small number of identifiers to encode a relatively large number of reaction products. For example, when used in a binary code, N identifiers can encode up to 2 N different compounds and/or conditions.
- identifiers which uniquely define the chosen variables such as reactant, reagent, reaction conditions, or combinations of these, one can use the identifiers to define the reaction history of each solid support.
- one begins with at least 10 3 , desirably at least 10 4 , and generally not exceeding 10 15 solid supports.
- the supports accordingly into as many containers.
- the appropriate reagents and reaction conditions are applied to each container and the combination of identifiers which encode for each R 1 /R 2 choice is added and attached.
- the tagging may be done prior to, concomitantly with, or after the reactions which comprise each choice.
- sample supports may be picked at any stage and a portion of their tags detached and decoded to verify that the correct tags are bound to the sample supports.
- the supports are usually combined, mixed, and again divided, this time into as many containers as pre determined for the number of choices for the second step in the synthesis. This procedure of dividing, reacting, tagging, and remixing is repeated until the combinatorial synthesis is completed.
- Functionalized supports such as amino-functionalized or hydroxy-terminating PEG grafted polystyrene beads are divided into a pre-determined number of reaction vessels and are reacted with a cleavable linker/ligand element 3, which has been pre-formed, to generate 4.
- Unique tagging of the supports in each reaction vessel is achieved with combinations of identifiers encoded in a binary scheme, e.g., as depicted in Table 1-1 for three choices of R 1 and R 2 .
- the identifiers are attached by adding a solution of the identifiers (in a 1.5% wt./wt. identifier:solid support ratio) to a batch of supports suspended in CH 2 Cl 2 and shaking the mixture for 30 min.
- Unique tagging of the supports in each reaction vessel is achieved with combinations of additional identifiers encoded in a binary scheme, e.g., as depicted in Table 1-2 for seven choices of R 4 R 5 .
- the compounds 5c where R 4 /R 5 /X represents the residue of piperidine, pyrrolidine, or aminocyclohexane, are pooled, mixed, and then divided into a pre-determined number of reaction vessels.
- the supports in each reaction vessel are uniquely tagged with combinations of additional identifiers encoded in a binary scheme, e.g., as depicted in Table 1-3 for 30 choices of R 8 and in Table 1-5 for six choices of R 14 and four choices of heteroaryl groups.
- each reaction vessel is treated with one reagent corresponding to ligand element R 8 in the presence of solvents such as CH 2 Cl 2 , DMF, or EtOH and, when required, bases such as triethylamine or 2,6-lutidine to produce 6 having an R 8 substituent at C-2 and a ketone at C-4, i.e., when R 6 R 7 together are O.
- R 14 is benzyl, -CH 2 -Ph-4-F, -CH 2 -Ph-4-OCH 3 , -CH 2 -4-Py, n-pentyl, or-CH 2 -c-propyl; and heteroaryl is , or
- a portion of the compounds 5a, 5b, 5c, and 6 may be pooled, mixed, and then divided into a pre-determined number of reaction vessels where they may be uniquely tagged with combinations of additional identifiers encoded in a binary scheme, e.g., as in Table 1-4 for three choices of R 6 /R 7 .
- Each vessel is treated with sodium borohydride to yield 7 as an alcohol at C-4 or is treated with 1,2-dithioethane and a Lewis acid such as BF 3 •Et 2 O to yield 8 as a dithiolane at C-4, or is treated with an appropriate non-beta branched primary amine in the presence of NaCNBH 3 in MeOH, optionally with acetic acid, to yield secondary amine 9, or is left untreated.
- a Lewis acid such as BF 3 •Et 2 O
- Compounds 5a, 5b, 5c, 5d, 6, 7, 8 , and 9 are then exposed to UV light (-360 nm) in polar solvents such as DMSO, H 2 O, or a lower alkanol such as MeOH to cleave the compounds of Formula II from the support/linker complex.
- polar solvents such as DMSO, H 2 O, or a lower alkanol such as MeOH to cleave the compounds of Formula II from the support/linker complex.
- TentaGel resin may be modified with bis-Boc Lysine to increase the available reaction sites for ligand attachment Bis-Boc-lysine in DMF, HOBt, and DIC are shaken at r.t. and then dry TentaGel resin is added. The mixture is shaken at r.t. for 17 hr and then washed alternately with methanol and DCM and then with THF and dried under vacuum. To deprotect the resin, DCM is added, followed by a 30 % TFA solution in DCM (100 mL). The vessel is shaken at room temperature for 15 min. before adding neat TFA.. The vessel is shaken at room temperature for 2.5 hr at which time the resin is washed with DCM, then treated with a solution of 10% triethylamine in DCM, then washed with DCM and DMF.
- Functionalized supports such as amino-functionalized or hydroxy-terminating PEG grafted polystyrene beads are divided into a pre-determined number of reaction vessels and are reacted with a cleavable linker/ligand element 10, which has been pre-formed, to generate 1 1.
- Unique tagging of the supports in each reaction vessel is achieved with combinations of identifiers encoded in a binary scheme, e.g., as depicted in Table 2-1 for seven choices of -(CH 2 ) 1-6 R 17 .
- the identifiers are attached by adding a solution of the identifiers (in a 7% wt./wt. identifie ⁇ solid support ratio) to each batch of supports suspended in EtOAc and shaking the mixture for 1 hr.
- a dilute solution of rhodium trifluoroacetate dimer in DCM is added and the mixture is shaken 15 hr and washed with DCM (4X) and EtOAc (2X). The procedure is repeated for each identifier.
- the compounds 12 are pooled, mixed, and divided into a pre-determined number of reaction vessels, each of which is treated with one acetophenone reagent corresponding to ligand element R 2 , in the presence of DIC, HOBt, and DMF to produce 4'.
- Unique tagging of the supports in each reaction vessel is achieved with combinations of additional identifiers encoded in a binary scheme analogous to that in
- the compounds 4' are mixed, pooled, and divided into a predetermined number of reaction vessels, each of which is treated with and aldehyde or ketone element corresponding to R 4 /R 5 in the presence of pyrrolidine in methanol at 75°C to produce the compounds 5a', 5b', and 5c'.
- Unique tagging of the supports in each reaction vessel is achieved with combinations of additional identifiers encoded in a binary scheme analogous to that in Table 2-1.
- R 4 /R 5 /X represents the residue of t-Boc protected piperidine, t-Boc protected aminocyclohexane, or other amine functionalized molecules are mixed, pooled, and divided into a predetermined number of reaction vessels.
- the supports in each reaction vessel are uniquely tagged with combinations of additional identifiers encoded in a binary scheme analogous to that in Table 2-1.
- each vessel is treated with one reagent such as a chloroformate, isocyanate,
- thioisocyanate carboxylic acid, alkyl or aryl sulfonyl halide, aldehyde, or a haloheteroaromatic compound corresponding to ligand element R 8 in the presence of solvents such as CH 2 Cl 2 , DMF, EtOH, or methanol.
- solvents such as CH 2 Cl 2 , DMF, EtOH, or methanol.
- bases such as triethylamine, DBU, or 2,6-lutidine and/or other reagents or combinations of reagents such as DIC,
- NaCNBH 3 , HOBt, and acetic acid are added to produce 6 ', having an R 8 substituent at C-2 and a ketone at C-4, i.e. when R 6 R 7 together are O.
- a portion of compounds 5a', 5b', 5c', and &. may be pooled, mixed, and then divided into a pre-determined number of reaction vessels where they may be uniquely tagged with combinations of additional identifiers encoded in a binary scheme analogous to that in Table 2-1.
- Each vessel is treated with 1) sodium borohydride in methanol to yield 7' as an alcohol at C-4; 2) 1 ,2-dithioethane and a Lewis acid such as boron trifluoride etherate to yield 81 as the dithiolane at C-4; 3) an unhindered primary amine along with
- the compounds 9 or 9 ' are divided into a predetermined number of reaction vessels.
- Each vessel is treated with one reagent such as a chloroformate, isocyanate, thioisocyanate, carboxylic acid, alkyl or aryl sulfonyl halide, aldehyde, or a haloheteroaromatic compound corresponding to ligand element R 15 in the presence of solvents such as CH 2 Cl 2 , DMF, EtOH, or methanol.
- bases such as triethylamine, DBU, or 2,6-lutidine and/or other reagents or
- Functionalized supports such as amino-functionalized or hydroxy-terminating PEG grafted polystyrene beads are placed into a reaction vessel and are reacted with a cleavable linker/ligand element 10, which has been pre-formed, to generate 1 1'.
- a cleavable linker/ligand element 10 which has been pre-formed, to generate 1 1'.
- To deprotect the resin it is suspended in DCM and ther agitated with a TFA solution in DCM. The resin is then washed with DCM followed by treatment with triethylamine in DCM and then washed with DCM to yield 12'.
- the amino resin 12' (1 equiv. of amino sites).
- a solvent such as DCM is added, followed by an organic base such as triethylamine, pyridine, Hiinig's base (di-isopropylethylamine), or 2,6-lutidine (10 equiv.).
- the resin is agitated for 4 hrs. and then washed with DCM and MeOH (5X each) to yield 14.
- n 3-12 and Ar is pentachlorophenyl or
- n 5-6 and Ar is 2,4,6-trichlorophenyl
- the crude material was dissolved in 100 mL toluene, 10 mL (1.63 g, 14 mmol ) thionyl chloride was added, and the mixture was refluxed for 90 min. The volume of the solution was reduced to approx. 30 mL by distillation, then the remaining toluene was removed by evaporation.
- Step (c) there is a change to the final diazomethylation step, whereby the ao.d chloride is reacted with (trimethylsilyl)diazomethane and triethylamine to give the identifier, which can then be used without further purification.
- the identifier can be obtained in high yield with no chloromethylketone byproduct. Also, purification by flash chromatography is no longer necessary, which in some cases has resulted in significant acid-catalyzed decomposition of the identifier.
- the other 11 identifiers of Formula IV were prepared by analogous synthetic routes, steps (a), (b), and (c).
- the 12 identifiers were used to encode the combinatorial library.
- pentachlorophenyl identifiers where n 8-10
- the acid (636 mg, 1.92 mmol, 1.5 equiv.) prepared above was dissolved in DMF (40 mL) and added to divinylbenzene-cross-linked, polyethyleneglycol-grafted polystyrene beads (TentaGel® S NH 2 , Rapp Polymere) (4.0 g, 0.32 mmol/g, 1.28 mmol, 1 equiv.) in a Merrifield reaction vessel. The resin was suspended by agitation, then HOBt (259 mg, 1.92 mmol, 1.5 equiv.) and DIC (0.31 mL, 1.92 mmol, 1.5 equiv.) were added in that order. The resin was agitated at room temperature for 7 hours at which time it gave a negative Kaiser test. The resin was filtered and washed (DMF 3 ⁇ 50 mL, DCM 3 ⁇ 50 mL) then dried in vacuo.
- DMF divinylbenzene-cross-linked, polyethyleneglycol-
- the two other dihydroxyacetophenones were attached to the resin via the photocleavable linker in an analogous manner using the reagents of Table 1-1.
- Rhodium trifluoroacetate dimer (1 mL of a 1 mg/mL solution in DCM) was added to each of the vessels and the resin was agitated at room temperature for 4 hours. Each batch of resin was then filtered and washed with DCM (2 ⁇ 20 mL) then each was resuspended in DCM (20 mL) and treated a second time with the appropriate binary encoding mixture as described above. The resin was again agitated for 30 mins before addition of the rhodium triflouroacetate dimer. The same quantities of catalyst and diazoketone compounds were used in the second coupling step as in the first. The resin was agitated for 14 hours. Each resin batch was then washed with DCM (5 ⁇ 20 mL) then the batches were combined and the entire library (three compounds) was washed with DCM (10 ⁇ 50 mL).
- the dried resin from Step 1(b) was divided into four batches of 1.5 g (c ⁇ . 0.42 mmol) and three additional batches of 0.2g (c ⁇ . 0.056 mmol).
- the 1.5g batches were placed into 25 mL round-bottomed flasks and the 0.2 g batches were placed into 5 mL round-bottomed flasks.
- the portions of resin were suspended in methanol (15 mL in the four flasks with 1.5 g of resin, 2 mL in the three flasks with 0.2 g of resin) and pyrrolidine (0.6 mL, 7.2 mmol, c ⁇ . 15 equiv.
- Each batch of resin from Step 2(a) was placed into a separate synthesis vessel and was suspended in DCM (5 mL for the batches of 1.5 g of resin, 1 mL for the batches containing 0.2 g of resin).
- the seven appropriate binary coding mixtures (see Table 1-2) for each batch of resin were prepared by dissolving the appropriate choice (22.5 mg if added to a batch of 1.5 g of resin; 3.0 mg if added to a batch of 0.2 g of resin) or choices (22.5 mg of each if added to a batch of 1.5 g of resin; 3.0 mg of each if added to a batch of 0.2 g of resin) of C 10 Cl 5 , C 9 Cl 5 , and C 8 Cl 5 linker-diazoketone (Preparation 1) in DCM (1 mL for each solution). These solutions were added to the appropriate synthesis vessel and the resin was agitated for 30 mins.
- Rhodium trifluoroacetate dimer (1 mL of a 1 mg/mL solution in DCM) was added to each of the vessels and the resin was agitated at room temperature for 4 hr. Each batch of resin was then filtered and washed with DCM (2 ⁇ 20 mL) then each was resuspended in DCM (5 mL for the batches of 1.5 g of resin, 1 mL for the batches of 0.2 g of resin) and treated a second time with the appropriate binary encoding mixture as described above. The resin was again agitated for thirty mins before addition of the rhodium trifluoroacetate dimer.
- Rhodium trifluoroacetate dimer (1 mL of a 1 mg/mL solution in DCM) was added to each of the vessels and the resin was agitated at room temperature for 4 hr. The supernatant solution was then decanted away from the resin with a Pasteur pipette. The resin was washed twice with DCM (3 mL) and the washings removed by Pasteur pipette. Each batch of resin was resuspended in DCM (2 mL) and treated a second time with the appropriate binary encoding mixture as described above. The resin was again agitated for thirty minutes before addition of the rhodium trifluoroacetate dimer.
- chloroformates were prepared from the appropriate alcohols by treating the alcohols (0.1 g) with a solution of phosgene in toluene (5 mL of a 1.8 M solution) for 1 hr, then evaporating to dryness in vacuo ,and then redissolving in DCM (5 mL).
- the flasks were filtered and the resin washed with DCM (3 ⁇ 10 mL). All of the resin was combined in one large synthesis vessel and was washed with DCM (3 ⁇ 50 mL), DMF (3 ⁇ 50 mL), and DCM again (3 ⁇ 50 mL). The resin was dried in vacuo.
- the remaining 900 mg of resin from the four combined batches of 1.5 g from Step 2(b) which had not been used in Step 3 was divided into ten portions of 90 mg, and each portion placed in a separate 1 dram shell vial (Fisher Scientific).
- the ten appropriate binary coding mixtures (see Table 1-5) for each batch of resin were prepared by dissolving the appropriate choice (1.5 mg) or choices (1.5 mg each) of C 7 Cl 5 , C 5 Cl 5 , C 4 Cl 5 , and C 3 Cl 5 linker-diazoketone (Preparation 1) in DCM (1 mL for each solution). These solutions were added to the appropriate synthesis vessels and the resin was agitated for 30 min.
- Rhodium trifluoroacetate dimer (1 mL of a 1 mg/mL solution in DCM) was added to each of the vessels and the resin was agitated at room temperature for 4 hr. The supernatant solution was then decanted from the resin. The resin was washed (DCM 2 ⁇ 3 mL) and the washings removed by Pasteur pipette. The resin was then treated a second time with solutions of the appropriate binary coding mixtures and agitated for 30 min. before the addition of the rhodium trifluoroacetate dimer. The same quantities of catalyst and diazoketone compounds were used in the second coupling as in the first. The batches of resin were then agitated for 16 hr. The resin was then transferred into small Merrifield synthesis vessels and washed (DCM 6 ⁇ 15 mL). b) Deprotection.
- Each batch of resin was treated with a solution of TFA in DCM (4 mL:4 mL). The resin was agitated for 1 hr, then filtered and washed with DCM (2 ⁇ 15 mL). The resin was then treated with a solution of piperidine in DCM (4 mL:4 mL) and agitated for 15 min. This treatment was repeated once. Each batch of beads was washed with methanol (2 ⁇ 15 mL) ana DCM (4 ⁇ 15 mL). Flasks 1-4 were washed with THF (3 ⁇ 15 mL).
- Flasks 1-3 were then treated wi ⁇ i DBU (190 ⁇ L, c ⁇ . 40 equiv.) followed by the appropriate heteroaryl chloride (c ⁇ . 20 equiv.). Flasks 1 and 2 were heated at 55 °C for 16 hr. Flask 3 was heated at reflux for 16 hr. Flask 4 was treated with triethylamine (700 ⁇ L) and the appropriate heteroaryl chloride (c ⁇ . 20 equiv.). The resin was shaken at r.t. for 16 hr. Each batch of resin was then washed in THF (2 ⁇ 15 mL) and dried in vacuo.
- THF 2 ⁇ 15 mL
- the resin in flasks 5-10 was suspended in DMF (8 mL) and the appropriate aldehyde (c ⁇ . 67 equiv.) added. Acetic acid (160 ⁇ L) was added to each of the flasks followed by sodium cyanoborohydride (c ⁇ . 67 equiv.). Flasks 5, 6, 7, 9, and 10 were shaken at r.t. for 16 hr. Flask 8 was heated to 55 °C for 16 hr. Each batch of resin was filtered and washed with DMF (3 ⁇ 15 mL). Each of the reductive alkylation reactions was repeated under the same conditions.
- the batches of resin were washed with DMF (2 ⁇ 15 mL), methanol (3 ⁇ 15 mL), and DCM (3 ⁇ 15 mL). The resin was then mixed, washed with DCM (2 ⁇ 20 mL), and dried in vacuo.
- Rhodium trifluoroacetate dimer (1 mL of a 1 mg/mL solution in DCM) was added to each of the vessels and the resin was agitated at room temperature for 4 hr. Each batch of resin was then filtered and washed with DCM (2 ⁇ 20 mL) then each was resuspended in DCM (10 mL) and treated a second time with the appropriate binary encoding mixture as described above. The resin was again agitated for 30 mins before addition of the rhodium trifluoroacetate dimer. The same quantities of catalyst and diazoketone compounds were used in the second coupling step as in the first. The resin was agitated for 14 hr.
- the resin in flask 2 was suspended in methanol (5 mL) and solid sodium borohydride (200 mg) was added cautiously. The flask was vented and allowed to shake gently for 1 hr. The resin was filtered and resuspended in methanol and the reduction process repeated a total of 5 times at 1 hr intervals using 200 mg of sodium borohydride each time. After the final cycle the resin was washed with methanol (3 ⁇ 20 mL) and DCM (3 ⁇ 20 mL).
- a bead was placed in a 1.3 mm diameter pyrex capillary with 2 ⁇ L of acetonitrile. Ceric ammonium nitrate solution (2 ⁇ L of a 0.1 M aq.. solution) and hexane (3 ⁇ L) were added and the two-phase mixture centrifuged briefly. The tube was sealed and left at 35 °C for 16 hrs, then opened. The organic layer was removed by syringe and mixed with 1 ⁇ L of N,O-bis(trimethylsilyl)acetamide. The silated tag solution (1 ⁇ L) was analyzed by GC with electron capture (EC) detection.
- EC electron capture
- the GC analysis was performed with a Hewlett Packard 5890 plus gas chromatograph. On column injection into a 5 m, 0.32 mm retention gap connected to a 25 m, 0.2 mm crosslinked 5% phenylmethyl silicone column was used.
- the temperature program was set at 200 °C for 1 min and then increased at a rate of 15°C/min from 200-320 °C.
- the pressure program was set at 20 psi for 1 min, then increased at 2 psi/min to 40 psi with a total run time of 10 min.
- the EC detector was maintained at 400 °C and the auxiliary gas was set at 35 psi.
- the six batches of encoded resin are combined in a 2 L Erlenmeyer flask along with THF (1 L) and mixed thoroughly by swirling and stirring gently with a glass rod. The resin is then recovered by filtration and vacuum dried.
- the mixed resin from Step 2 is divided into three batches of 14.4 g (c ⁇ . 8.1 mmol) and seven additional batches of 1.5 g (c ⁇ . 0.84 mmol).
- the 14.4 g batches are placed into 250 mL round bottom flasks and the 1.5 g batches are placed in 25 mL round bottom flasks.
- the portions of resin are suspended in methanol (150 mL in the three flasks with 14.4 g resin, 15 mL in the seven flasks with 1.5 g resin) and pyrrolidine (10.1 mL, 121 mmol, c ⁇ . 15 equiv. in the flasks with 14.4 g resin; 1.0 mL, 12.6 mmol, c ⁇ . 15 equiv.
- Step 4 500 mL Erlenmeyer flask along with THF (250 mL) and mixed thoroughly by swirling and stirring gently with a glass rod. The resin is then recovered by filtration and vacuum dried. This combined resin is kept separate from the three 14.4 g batches of resin and is not subjected to the reaction conditions of Step 4, but rather re-divided into three 0.2 g portions and seven 1.4 g portions and saved to be used in Step 5 and alternate Step 5. The three 14.4 g batches of encoded resin are combined in a 2 L Erlenmeyer flask along with THF (1 L) and mixed thoroughly by swirling and stirring gently with a glass rod. The resin is then recovered by filtration, vacuum dried, and used in Step 4.
- cyanoborohydnde (c ⁇ . 50 equiv.) is added and the resin agitated for 16 hr.
- the resin is washed with alternating DCM and methanol (5X each) and then with EtOAc (2X).
- the resin from the sixth of the seven 250 mL synthesis vessels containing deprotected resin from Step 4(a) (6 g, c ⁇ . 3.4 mmol) is transferred to a 250 mL round bottom flask. THF (150 mL) is added followed by DBU (c ⁇ . 40 equiv.). 2-Chloropyrimidine (c ⁇ . 20 equiv.) is added. The mixture is heated to 55°C for 16 hr. The resin is transferred back to a 250 mL synthesis vessel, washed with alternating DCM and methanol (5X each), and then with EtOAc (2X).
- Each of the seven batches of resin from Step 4(b) are binariiy encoded in a fashion analogous to that described for the encoding of Step 1.
- the seven encoded 5.7 g. batches of resin from Step 5(a) are placed in 200 mL round bottom flasks.
- the seven encoded 1.4 g. batches from Step 3(c) are placed in 50 mL round bottom flasks.
- To each of the fourteen flasks is added a solution of 10% glacial acetic acid in methanol (60 mL in the 200 mL flasks, 15 mL in the 50 mL flasks).
- the appropriate amine from Table 2-6 (c ⁇ . 40 equiv.) is added followed by sodium cyanoborohydride (c ⁇ . 40 equiv.).
- Condensers are attached and the mixtures are heated to 75°C for 48 hr.
- the resin is washed with alternating DCM and methanol (5X each) and then with EtOAc (2X).
- Step 6(a) total of c ⁇ . 32.5 g. is divided into ten 3.2 g.
- N,N'-bis Boc-(L)-lysine (c ⁇ . 10 equiv.) as a solution in DMF (60 mL in the larger vessel, 15 mL in the smaller).
- HOBt (c ⁇ . 15 equiv.) is added and the resin agitated for 15 min.
- DIC (c ⁇ . 10 equiv.) is added and the resin agitated for 4 hr.
- the resin is washed with DCM (2X) and then treated with TFA (30% solution in DCM) (1.5 hrs.).
- the resin is then washed with DCM (2X) and treated with 10% triethylamine in DMF (2X, 30 min. each).
- the resin is washed with alternating DCM and methanol (5X each) and then with EtOAc (2X).
- N- ⁇ -Fmoc-N- ⁇ -Pmc-(L)-arginine (c ⁇ . 10 equiv.) as a solution in DMF (60 mL in the larger vessel, 15 mL in the smaller).
- HOBt (c ⁇ .. 15 equiv.) is added and the resin agitated for 15 min..
- DIC (c ⁇ . 10 equiv.) is added and the resin agitated for 4 hr.
- the resin is washed with DCM (2X) and then treated with TFA (50% solution in DCM) (1.5 hrs.).
- the resin is then washed with DCM (2X) and treated with 50% piperidine in DMF (2X, 30 min. each).
- the resin is washed with alternating DCM and methanol (5X each) and then with EtOAc (2X).
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95920411A EP0758313A4 (fr) | 1994-05-06 | 1995-05-08 | Bibliotheque combinatoire de dihydrobenzopyranes |
JP7529207A JPH10500112A (ja) | 1994-05-06 | 1995-05-08 | 組合せ ジヒドロベンゾピラン ライブラリー |
AU25869/95A AU691296B2 (en) | 1994-05-06 | 1995-05-08 | Combinatorial dihydrobenzopyran library |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US23930294A | 1994-05-06 | 1994-05-06 | |
US08/239,302 | 1994-05-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995030642A1 true WO1995030642A1 (fr) | 1995-11-16 |
Family
ID=22901570
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1995/005940 WO1995030642A1 (fr) | 1994-05-06 | 1995-05-08 | Bibliotheque combinatoire de dihydrobenzopyranes |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0758313A4 (fr) |
JP (1) | JPH10500112A (fr) |
AU (1) | AU691296B2 (fr) |
CA (1) | CA2189634A1 (fr) |
WO (1) | WO1995030642A1 (fr) |
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US6610489B2 (en) | 2000-04-28 | 2003-08-26 | Sangamo Biosciences, Inc. | Pharmacogenomics and identification of drug targets by reconstruction of signal transduction pathways based on sequences of accessible regions |
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US6790965B1 (en) | 1994-05-06 | 2004-09-14 | Pharmacopeia Drug Discovery, Inc. | Combinatorial dihydrobenzopyran library |
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US7217509B2 (en) | 2000-04-28 | 2007-05-15 | Sangamo Biosciences, Inc. | Databases of regulatory sequences; methods of making and using same |
WO2007054580A1 (fr) * | 2005-11-14 | 2007-05-18 | Solvay Pharmaceuticals Gmbh | N-sulfamoyl-n’-benzopyranpipéridines en tant qu'inhibiteurs d'anhydridases carboniques |
WO2007103374A2 (fr) | 2006-03-06 | 2007-09-13 | Ceetox, Inc | Procedes de depistage de la toxicite |
WO2008042024A2 (fr) | 2006-06-01 | 2008-04-10 | Elan Pharmaceuticals, Inc. | Fragments neuroactifs de app |
WO2008088692A2 (fr) | 2007-01-12 | 2008-07-24 | Merck & Co., Inc. | Dérivés spirochromanone |
WO2008088688A1 (fr) | 2007-01-12 | 2008-07-24 | Merck & Co., Inc. | Dérivés substitués de spirochromanone en tant qu'inhibiteurs d'acc |
US7410976B2 (en) | 2005-07-19 | 2008-08-12 | Merck & Co., Inc. | Spirochromanone derivatives |
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US7507546B2 (en) | 2001-06-11 | 2009-03-24 | Xenoport, Inc. | Methods of screening agents, conjugates or conjugate moieties for transport by a PEPT2 transporter |
US7547708B2 (en) | 2005-11-14 | 2009-06-16 | Solvay Pharmaceuticals, Inc. | N-sulfamoyl-N′-benzopyranpiperidine compounds and uses thereof |
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WO2009086539A2 (fr) | 2007-12-28 | 2009-07-09 | Elan Pharmaceuticals, Inc. | Traitement et prophylaxie de l'amylose |
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US7572600B2 (en) | 2004-08-04 | 2009-08-11 | Chemocentryx, Inc. | Enzymatic activities in chemokine-mediated inflammation |
WO2010021415A1 (fr) | 2008-08-18 | 2010-02-25 | Seoul National University Industry Foundation | Procédé pour la lutte contre la métastase cancéreuse ou la migration de cellules cancéreuses par modulation du taux cellulaire de lysyl-arnt synthétase |
US7863029B2 (en) | 2004-06-04 | 2011-01-04 | Fox Chase Cancer Center | Alternate morpheeins of allosteric proteins as a target for the development of bioactive molecules |
EP2272539A2 (fr) | 2004-10-19 | 2011-01-12 | Elan Pharmaceuticals, Inc. | Fragments tronqués d'alpha-synucléines dans une maladie de corps de Lewy |
US7887753B2 (en) | 2000-11-16 | 2011-02-15 | California Institute Of Technology | Apparatus and methods for conducting assays and high throughput screening |
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US7923542B2 (en) | 2000-04-28 | 2011-04-12 | Sangamo Biosciences, Inc. | Libraries of regulatory sequences, methods of making and using same |
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US8153410B2 (en) | 2003-07-07 | 2012-04-10 | Fox Chase Cancer Center | Alternate morpheein forms of allosteric proteins as a target for the development of bioactive molecules |
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Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004092179A1 (fr) * | 2003-04-14 | 2004-10-28 | Nippon Soda Co. Ltd. | Derive spiro, procede de production et antioxydant |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4499299A (en) * | 1981-12-30 | 1985-02-12 | Ici Americas Inc. | Pharmaceutically active phenylcarboxylic acid derivatives |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4838924A (en) * | 1985-08-05 | 1989-06-13 | Mitsui Petrochemical Industries, Ltd. | Aromatic urea derivatives and their use as herbicide |
WO1994008051A1 (fr) * | 1992-10-01 | 1994-04-14 | The Trustees Of Columbia University In The City Of New York | Banques chimiques combinatoires complexes codees avec des etiquettes |
-
1995
- 1995-05-08 JP JP7529207A patent/JPH10500112A/ja active Pending
- 1995-05-08 AU AU25869/95A patent/AU691296B2/en not_active Ceased
- 1995-05-08 WO PCT/US1995/005940 patent/WO1995030642A1/fr not_active Application Discontinuation
- 1995-05-08 EP EP95920411A patent/EP0758313A4/fr not_active Withdrawn
- 1995-05-08 CA CA002189634A patent/CA2189634A1/fr not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4499299A (en) * | 1981-12-30 | 1985-02-12 | Ici Americas Inc. | Pharmaceutically active phenylcarboxylic acid derivatives |
Non-Patent Citations (3)
Title |
---|
ABSTRACT, MITSUI PETROCHEMICAL INDUSTRIES, Abstract 236509B; & WO,A,87 00840, February 1987. * |
J. MED. CHEM., Volume 32, Number 4, issued April 1989, BROWN et al., "Hydroxyacetophenone-Derived Antagonists of the Peptidoleukotrienes", pages 807-826. * |
See also references of EP0758313A4 * |
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US6521780B1 (en) | 1996-03-15 | 2003-02-18 | Basf Aktiengesellschaft | Cycloalkyl derivatives and the solid-phase synthesis of such derivatives |
US6242583B1 (en) | 1996-05-24 | 2001-06-05 | Basf Aktiengesellschaft | Carbohydrate derivatives and their solid-phase synthesis |
US6271345B1 (en) | 1996-07-03 | 2001-08-07 | Basf Aktiengesellschaft | Enzyme cleavable linker bound to solid phase for organic compound synthesis |
WO1998008835A1 (fr) * | 1996-08-26 | 1998-03-05 | Pfizer Inc. | Ligands spirocycliques d'un sous-type du recepteur de la dopamine |
US6664258B1 (en) | 1996-08-26 | 2003-12-16 | Pfizer Inc | Spirocyclic dopamine receptor subtype ligands |
US6004823A (en) * | 1997-05-07 | 1999-12-21 | Smithkline Beecham Corporation | Compounds |
US5908960A (en) * | 1997-05-07 | 1999-06-01 | Smithkline Beecham Corporation | Compounds |
WO1999015894A3 (fr) * | 1997-09-25 | 1999-08-19 | Cerep | Procede d'identification de composes selectionnes apres au moins deux etapes de criblage ou de composes actifs |
WO1999015894A2 (fr) * | 1997-09-25 | 1999-04-01 | Cerep | Procede d'identification de composes selectionnes apres au moins deux etapes de criblage ou de composes actifs |
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US6362009B1 (en) | 1997-11-21 | 2002-03-26 | Merck & Co., Inc. | Solid phase synthesis of heterocycles |
EP2305282A2 (fr) | 1997-12-02 | 2011-04-06 | Janssen Alzheimer Immunotherapy | Prévention et traitement de maladie amyloidogène |
EP1994937A2 (fr) | 1997-12-02 | 2008-11-26 | Elan Pharma International Limited | Prévention et traitement de maladie amyloidogénique |
JP2001526390A (ja) * | 1997-12-12 | 2001-12-18 | アボット・ラボラトリーズ | 連続フォーマット高スループットスクリーニング |
WO2000032773A1 (fr) | 1998-11-27 | 2000-06-08 | Darwin Discovery Ltd. | Compositions et methodes d'augmentation de la mineralisation de la substance osseuse |
EP2261335A1 (fr) | 1998-11-27 | 2010-12-15 | UCB Pharma S.A. | Compositions et méthodes pour augmenter la minéralisation des os. |
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US7923542B2 (en) | 2000-04-28 | 2011-04-12 | Sangamo Biosciences, Inc. | Libraries of regulatory sequences, methods of making and using same |
WO2001083751A2 (fr) | 2000-04-28 | 2001-11-08 | Sangamo Biosciences, Inc. | Methodes de fixation d"une molecule exogene a la chromatine cellulaire |
US6511808B2 (en) | 2000-04-28 | 2003-01-28 | Sangamo Biosciences, Inc. | Methods for designing exogenous regulatory molecules |
US6610489B2 (en) | 2000-04-28 | 2003-08-26 | Sangamo Biosciences, Inc. | Pharmacogenomics and identification of drug targets by reconstruction of signal transduction pathways based on sequences of accessible regions |
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US8673645B2 (en) | 2000-11-16 | 2014-03-18 | California Institute Of Technology | Apparatus and methods for conducting assays and high throughput screening |
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US7919454B2 (en) | 2001-06-11 | 2011-04-05 | Xenoport, Inc. | Methods of treating using conjugates transported by a PEPT2 transporter |
US7507546B2 (en) | 2001-06-11 | 2009-03-24 | Xenoport, Inc. | Methods of screening agents, conjugates or conjugate moieties for transport by a PEPT2 transporter |
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WO2004041067A2 (fr) | 2002-11-01 | 2004-05-21 | Elan Pharmaceuticals, Inc. | Prevention et traitement d'une maladie synucleopathique |
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WO2004048552A2 (fr) | 2002-11-21 | 2004-06-10 | Celltech R & D, Inc. | Modulation de reponses immunitaires |
WO2004050895A2 (fr) | 2002-11-27 | 2004-06-17 | Irm Llc | Procedes et compositions induisant l'apoptose de cellules cancereuses |
WO2004069182A2 (fr) | 2003-02-01 | 2004-08-19 | Neuralab Limited | Immunisation active permettant de produire des anticorps contre a-beta soluble |
EP2361928A1 (fr) | 2003-05-19 | 2011-08-31 | Elan Pharmaceuticals Inc. | Fragments tronqués d'alpha-synucléines dans une maladie de corps de Lewy |
EP2341071A1 (fr) | 2003-06-16 | 2011-07-06 | UCB Manufacturing, Inc. | Compositions et méthodes pour l'augmentation de la minéralisation des os |
EP2338906A1 (fr) | 2003-06-16 | 2011-06-29 | UCB Manufacturing, Inc. | Compositions et méthodes pour l'augmentation de la mineralisation des os |
US8153410B2 (en) | 2003-07-07 | 2012-04-10 | Fox Chase Cancer Center | Alternate morpheein forms of allosteric proteins as a target for the development of bioactive molecules |
JP2007507532A (ja) * | 2003-10-01 | 2007-03-29 | アドラー コーポレーション | スピロ環複素環誘導体及びそれらを使用する方法 |
US8187874B2 (en) | 2003-10-27 | 2012-05-29 | Vertex Pharmaceuticals Incorporated | Drug discovery method |
EP2336147A2 (fr) | 2003-12-17 | 2011-06-22 | Janssen Alzheimer Immunotherapy | Conjugués transporteur de peptides bêta immunogènes et leurs procédés de production |
EP2479184A2 (fr) | 2003-12-17 | 2012-07-25 | Janssen Alzheimer Immunotherapy | Conjugués transporteurs de peptides bêta immunogènes et leurs procédés de production |
EP2460813A1 (fr) | 2003-12-17 | 2012-06-06 | Janssen Alzheimer Immunotherapy | Conjugués transporteurs de peptides bêta immunogènes et leurs procédés de production |
WO2005058940A2 (fr) | 2003-12-17 | 2005-06-30 | Wyeth | Conjugues porteurs de peptides immunogenes et procedes de production associes |
US7863029B2 (en) | 2004-06-04 | 2011-01-04 | Fox Chase Cancer Center | Alternate morpheeins of allosteric proteins as a target for the development of bioactive molecules |
US7572600B2 (en) | 2004-08-04 | 2009-08-11 | Chemocentryx, Inc. | Enzymatic activities in chemokine-mediated inflammation |
EP3369433A1 (fr) | 2004-08-09 | 2018-09-05 | Janssen Alzheimer Immunotherapy | Prévention et traitement de la maladie synucléinopathique et amyloidogénique |
WO2006020581A2 (fr) | 2004-08-09 | 2006-02-23 | Elan Pharmaceuticals, Inc. | Prevention et traitement de maladies synucleinopathique et amyloidogenique |
EP2371396A1 (fr) | 2004-10-19 | 2011-10-05 | Elan Pharmaceuticals Inc. | Fragments tronqués d'alpha-synucléines dans une maladie de corps de Lewy |
EP2272539A2 (fr) | 2004-10-19 | 2011-01-12 | Elan Pharmaceuticals, Inc. | Fragments tronqués d'alpha-synucléines dans une maladie de corps de Lewy |
EP2302076A1 (fr) | 2005-02-14 | 2011-03-30 | University of Iowa Research Foundation | Procédés et réactifs pour le traitement et le diagnostic de la dégénération maculaire liée à l'âge |
EP2357254A1 (fr) | 2005-02-14 | 2011-08-17 | University of Iowa Research Foundation | Biomarqueurs associés à la dégénérescence maculaire liée à l'âge |
WO2006088950A2 (fr) | 2005-02-14 | 2006-08-24 | University Of Iowa Research Foundation | Procedes et reactifs pour le traitement et le diagnostic de la degenerescence maculaire liee a l'age |
US7410976B2 (en) | 2005-07-19 | 2008-08-12 | Merck & Co., Inc. | Spirochromanone derivatives |
US7935712B2 (en) | 2005-07-19 | 2011-05-03 | Merck Sharp & Dohme Corp. | Spirochromanone derivatives as acetyl coenzyme A carboxylase (ACC) inhibitors |
EP2450056A1 (fr) | 2005-07-19 | 2012-05-09 | Elan Pharma International Limited | Prévention et traitement de la maladie synucléinopathique et amyloidogénique |
US8193328B2 (en) | 2005-09-08 | 2012-06-05 | Philadelphia Health & Education Corporation | Identification of modulators of serine protease inhibitor Kazal and their use as anti-cancer and anti-viral agents |
WO2007054580A1 (fr) * | 2005-11-14 | 2007-05-18 | Solvay Pharmaceuticals Gmbh | N-sulfamoyl-n’-benzopyranpipéridines en tant qu'inhibiteurs d'anhydridases carboniques |
US7547708B2 (en) | 2005-11-14 | 2009-06-16 | Solvay Pharmaceuticals, Inc. | N-sulfamoyl-N′-benzopyranpiperidine compounds and uses thereof |
WO2007103374A2 (fr) | 2006-03-06 | 2007-09-13 | Ceetox, Inc | Procedes de depistage de la toxicite |
EP2287327A1 (fr) | 2006-03-06 | 2011-02-23 | Ceetox Inc. | Procédés in vitro de dépistage de la toxicité de médicament antitumoral |
WO2008042024A2 (fr) | 2006-06-01 | 2008-04-10 | Elan Pharmaceuticals, Inc. | Fragments neuroactifs de app |
WO2008088692A2 (fr) | 2007-01-12 | 2008-07-24 | Merck & Co., Inc. | Dérivés spirochromanone |
US8093389B2 (en) | 2007-01-12 | 2012-01-10 | Merck Sharp & Dohme Corp. | Substituted spirochromanone derivatives |
WO2008088688A1 (fr) | 2007-01-12 | 2008-07-24 | Merck & Co., Inc. | Dérivés substitués de spirochromanone en tant qu'inhibiteurs d'acc |
US8138197B2 (en) | 2007-01-12 | 2012-03-20 | Msd K.K. | Spirochromanon derivatives |
EP3067066A1 (fr) | 2007-02-23 | 2016-09-14 | Prothena Biosciences Limited | Prevention et traitement de la maladie synucleinopathique et amyloidogenique |
EP2583978A2 (fr) | 2007-02-23 | 2013-04-24 | The Regents of the University of California | Prévention et traitement de maladie synucléopathique et amyloidogénique |
WO2009078799A1 (fr) | 2007-12-17 | 2009-06-25 | Marfl Ab | Nouveau vaccin pour le traitement de troubles liés à une mycobactérie |
US8779088B2 (en) | 2007-12-17 | 2014-07-15 | Marfl Ab | Vaccine for the treatment of Mycobacterium related disorders |
EP2730659A2 (fr) | 2007-12-28 | 2014-05-14 | Elan Pharmaceuticals Inc. | Traitement et Prophylaxie de L'amylose |
US8268973B2 (en) | 2007-12-28 | 2012-09-18 | Onclave Therapeutics | Anti-amyloid antibodies |
US7928203B2 (en) | 2007-12-28 | 2011-04-19 | Elan Pharmaceuticals, Inc. | Chimeric, humanized, or human antibody 2A4 |
US8791243B2 (en) | 2007-12-28 | 2014-07-29 | Onclave Therapeutics Limited | Treatment and prophylaxis of amyloidosis |
US8636981B2 (en) | 2007-12-28 | 2014-01-28 | Onclave Therapeutics | Detection of amyloid deposits using anti-amyloid antibodies |
WO2009086539A2 (fr) | 2007-12-28 | 2009-07-09 | Elan Pharmaceuticals, Inc. | Traitement et prophylaxie de l'amylose |
EP3693470A1 (fr) | 2007-12-28 | 2020-08-12 | Prothena Therapeutics Limited | Traitement et prophylaxie de l'amylose |
US8404815B2 (en) | 2007-12-28 | 2013-03-26 | Onclave Therapeutics | Chimeric, humanized, or human antibody 2A4 |
US8962912B2 (en) | 2007-12-31 | 2015-02-24 | Baxter International Inc. | Transgenic non-human animals expressing human blood clotting factors and uses thereof |
WO2009091586A2 (fr) | 2008-01-18 | 2009-07-23 | North Carolina State University | Peptides et méthodes d'utilisation comme agents thérapeutiques et agents de criblage |
US8524730B2 (en) | 2008-07-04 | 2013-09-03 | Msd K.K. | Spirochromanone carboxylic acids |
WO2010021415A1 (fr) | 2008-08-18 | 2010-02-25 | Seoul National University Industry Foundation | Procédé pour la lutte contre la métastase cancéreuse ou la migration de cellules cancéreuses par modulation du taux cellulaire de lysyl-arnt synthétase |
US10336717B2 (en) | 2009-03-13 | 2019-07-02 | Vitae Pharmaceuticals, Llc | Inhibitors of beta-secretase |
US9212153B2 (en) | 2009-03-13 | 2015-12-15 | Vitae Pharmaceuticals, Inc. | Inhibitors of beta-secretase |
US8969255B2 (en) | 2009-06-19 | 2015-03-03 | The Arizona Board Of Regents | Compound arrays for sample profiling |
US10422793B2 (en) | 2009-06-19 | 2019-09-24 | Arizona Board Of Regents On Behalf Of Arizona State University | Compound arrays for sample profiling |
US9709558B2 (en) | 2009-06-19 | 2017-07-18 | Arizona Board Of Regents On Behalf Of Arizona State University | Compound arrays for sample profiling |
US8889703B2 (en) | 2010-02-24 | 2014-11-18 | Vitae Pharmaceuticals, Inc. | Inhibitors of beta-secretase |
US8598164B2 (en) | 2010-05-06 | 2013-12-03 | Vertex Pharmaceuticals Incorporated | Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels |
US8916565B2 (en) | 2011-02-02 | 2014-12-23 | Vertex Pharmaceuticals Incorporated | Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels |
US9511067B2 (en) | 2011-02-02 | 2016-12-06 | Vertex Pharmaceuticals Incorporated | Substituted spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]s as modulators of ion channels |
US10385070B2 (en) | 2011-02-18 | 2019-08-20 | Vertex Pharmaceuticals Incorporated | Chroman-spirocyclic piperidine amides as modulators of ion channels |
US9181273B2 (en) | 2011-03-14 | 2015-11-10 | Vertex Pharmaceuticals Incorporated | Morpholine-spirocyclic piperidine amides as modulators of ion channels |
US8828996B2 (en) | 2011-03-14 | 2014-09-09 | Vertex Pharmaceuticals Incorporated | Morpholine-spirocyclic piperidine amides as modulators of ion channels |
US8975293B2 (en) | 2011-05-26 | 2015-03-10 | Regents Of The University Of Michigan | Epigenetic co-repressors of the gamma-globin gene and methods of using same |
US9435807B2 (en) | 2011-09-22 | 2016-09-06 | Medicinal Bioconvergence Research Center | Use of leucyl tRNA synthetase |
US9678062B2 (en) | 2011-09-23 | 2017-06-13 | University Of Louisville Research Foundation, Inc. | Methods and compositions for expanding cells and improving engraftment |
US9274113B2 (en) | 2011-10-10 | 2016-03-01 | Medicinal Bioconvergence Research Center | Method for screening an agent preventing or treating cancer using glycyl-tRNA synthetase and cadherin |
WO2013055101A1 (fr) | 2011-10-10 | 2013-04-18 | Medicinal Bioconvergence Research Center | Procédé de criblage à la recherche d'un agent de prévention ou de traitement du cancer en utilisant une glycyl-arnt synthétase et une cadhérine |
WO2013078138A1 (fr) | 2011-11-21 | 2013-05-30 | OSI Pharmaceuticals, LLC | Spectroscopie rmn du proton pour criblage biochimique |
US9526727B2 (en) | 2012-03-05 | 2016-12-27 | Vitae Pharmaceutical, Inc. | Inhibitors of beta-secretase |
US8981112B2 (en) | 2012-03-05 | 2015-03-17 | Vitae Pharmaceuticals, Inc. | Inhibitors of β-secretase |
US9949975B2 (en) | 2012-03-05 | 2018-04-24 | Vitae Pharmaceuticals, Inc. | Inhibitors of beta-secretase |
US9018391B2 (en) | 2012-08-27 | 2015-04-28 | Boehringer Ingelheim International Gmbh | Inhibitors of beta-secretase |
US9290477B2 (en) | 2012-09-28 | 2016-03-22 | Vitae Pharmaceuticals, Inc. | Inhibitors of β-secretase |
US11067582B2 (en) | 2013-03-15 | 2021-07-20 | Arizona Board Of Regents On Behalf Of Arizona State University | Peptide array quality control |
US9970932B2 (en) | 2013-03-15 | 2018-05-15 | Arizona Board Of Regents On Behalf Of Arizona State University | Non-covalent patterned chemical features and use thereof in MALDI-based quality control |
US10006919B2 (en) | 2013-03-15 | 2018-06-26 | Arizona Board Of Regents On Behalf Of Arizona State University | Peptide array quality control |
US10578623B2 (en) | 2013-03-15 | 2020-03-03 | Arizona Board of Regents of behalf of Arizona State University | Peptide array quality control |
EP4219564A1 (fr) | 2014-09-12 | 2023-08-02 | The Board of Trustees of the Leland Stanford Junior University | Molécules d'agonistes de la signalisation wn |
WO2016040895A1 (fr) | 2014-09-12 | 2016-03-17 | xxTHE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY | Molécules d'agonistes de la signalisation wnt |
WO2016100857A1 (fr) | 2014-12-19 | 2016-06-23 | Regeneron Pharmaceuticals, Inc. | Cellules souches comme modèle du diabète de type 2 |
US10758886B2 (en) | 2015-09-14 | 2020-09-01 | Arizona Board Of Regents On Behalf Of Arizona State University | Conditioned surfaces for in situ molecular array synthesis |
WO2017208210A1 (fr) | 2016-06-03 | 2017-12-07 | Prothena Biosciences Limited | Anticorps anti-mcam et methodes d'utilisation associées |
US11774446B2 (en) | 2016-06-20 | 2023-10-03 | Cowper Sciences Inc. | Methods for diagnosis and treatment of autoimmune diseases |
US11747334B2 (en) | 2016-06-20 | 2023-09-05 | Cowper Sciences Inc. | Methods for differential diagnosis of autoimmune diseases |
WO2018007979A1 (fr) | 2016-07-06 | 2018-01-11 | Prothena Biosciences Limited | Essai pour la détection d'alpha-synucléine totale et phosphorylée sur s129 |
WO2018023014A1 (fr) | 2016-07-29 | 2018-02-01 | Regeneron Pharmaceuticals, Inc. | Souris comprenant des mutations entraînant l'expression de la fibrilline 1 tronquée en c |
WO2018071493A1 (fr) | 2016-10-12 | 2018-04-19 | Janssen Biotech, Inc. | Procédés de criblage de modulateurs d'une activité biologique de type gdf15 |
US11371990B2 (en) | 2016-11-11 | 2022-06-28 | Cowper Sciences Inc. | Methods for identifying candidate biomarkers |
WO2018202850A1 (fr) | 2017-05-05 | 2018-11-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Médicaments ciblant les microtubules en tant qu'inhibiteurs de points de contrôle immunitaires et procédés de criblage de nouveaux inhibiteurs de points de contrôle immunitaires pour le traitement de cancers et de maladies infectieuses |
US11971410B2 (en) | 2017-09-15 | 2024-04-30 | Arizona Board Of Regents On Behalf Of Arizona State University | Methods of classifying response to immunotherapy for cancer |
US12025615B2 (en) | 2017-09-15 | 2024-07-02 | Arizona Board Of Regents On Behalf Of Arizona State University | Methods of classifying response to immunotherapy for cancer |
WO2019094735A1 (fr) | 2017-11-10 | 2019-05-16 | Regeneron Pharmaceuticals, Inc. | Animaux non humains comprenant une mutation de slc30a8 et procédés d'utilisation |
WO2020016433A1 (fr) | 2018-07-20 | 2020-01-23 | Aicuris Gmbh & Co. Kg | Procédés de criblage et d'identification d'agents inhibant ou modulant le complexe de sortie nucléaire du virus de l'herpès |
WO2020210724A1 (fr) | 2019-04-10 | 2020-10-15 | University Of Utah Research Foundation | Modulation de htra1 pour le traitement de la dmla |
US11976274B2 (en) | 2019-10-02 | 2024-05-07 | Arizona Board Of Regents On Behalf Of Arizona State University | Methods and compositions for identifying neoantigens for use in treating and preventing cancer |
US12018252B2 (en) | 2019-10-02 | 2024-06-25 | Arizona Board Of Regents On Behalf Of Arizona State University | Methods and compositions for identifying neoantigens for use in treating cancer |
WO2022235929A1 (fr) | 2021-05-05 | 2022-11-10 | Radius Pharmaceuticals, Inc. | Modèle animal ayant une recombinaison homologue du récepteur pth1 de souris |
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JPH10500112A (ja) | 1998-01-06 |
EP0758313A1 (fr) | 1997-02-19 |
AU2586995A (en) | 1995-11-29 |
CA2189634A1 (fr) | 1995-11-16 |
AU691296B2 (en) | 1998-05-14 |
EP0758313A4 (fr) | 1999-09-15 |
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